Chronic fatigue syndrome is a difficult to diagnose, ubiquitous disorder characterized by extreme fatigue, lymph gland enlargement and constitutional symptoms such as weight loss, loss of appetite, memory deterioration and loss of intelligence in some patients. Some CFS patients manifest neuropsychiatric changes such as depression, loss of memory and similar derangements. Thus, chronic fatigue syndrome is sometimes difficult to distinguish from entirely neurological disorders, particularly situational depression. An accumulating body of evidence suggests that CFS is associated with disregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer cell function and changes in intermediary metabolites. It has been suggested that the clinical and immunological abnormalities observed in CFS might include defects in the double-stranded RNA (dsRNA)-dependent, interferon-inducible pathways, the 2′,5′-oligoadenylate (2-5A) synthetase/RNase L and p68 kinase (PKR) antiviral defense pathways (Suhadolnik et al., Clin. Infect. Dis. 18: S96-S104, 1994; Suhadolnik et al., In Vivo 8: 599-604, 1994).
Gamma-retroviruses are a genus of the retroviridae family. A retrovirus is an RNA virus that is replicated in a host cell via the enzyme reverse transcriptase to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA. Gamma-retroviruses include amongst others the murine leukemia virus (MLV) that causes cancer in murine hosts and may infect other vertebrates and the feline leukemia virus (FeLV) that infects cats. Xenotropic murine leukemia virus-related virus (XMRV) is an infectious human gamma-retrovirus. Recently, it has been suggested that XMRV may be a contributing factor in the pathogenesis of CFS. Studying peripheral blood mononuclear cells from CFS patients, DNA from XMRV was identified in 67% of patients as compared with 3.7% of healthy controls (Lombardi et al., Science 23; 326(5952): 585-9, 2009). Furthermore, MLV-related virus gene sequences were found in 86.5% of patients meeting accepted diagnostic criteria for CFS compared with 6.8% of healthy blood donors (Shyh-Ching et al., PNAS 107; 36: 15874-79, 2010). It is noted however that these results were not reproduced by successive studies. XMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK (Erlwein et al., PLoS One 5(1): e8519, 2010). Moreover, no evidence of infection with XMRV was found in a US study population of CFS patients or healthy controls by using multiple molecular and serologic assays (Switzer et al., Retrovirology 7(1): 57, 2010). In addition, no association between XMRV infection and CFS was observed in samples from CFS patients from two UK cohorts and from controls tested, either by PCR or serological methodologies (Groom et al., Retrovirology 7: 10, 2010). Therefore, the role of XMRV in the pathogenesis of CFS remains to be clarified.
The 2-5A synthetase/RNase L pathway is part of the antiviral defense mechanism in mammalian cells. During viral infection, 2-5A synthetase is activated by dsRNA, derived from viral replicative intermediates. Activated 2-5A synthetase converts ATP to 2′,5′-linked oligoadenylates. Biologically active 2-5A binds to and activates a latent endoribonuclease, RNase L, leading to its dimerization and activation. Activated RNase L hydrolyzes single-stranded viral and cellular RNA, thereby inhibiting protein synthesis.
Many viruses have evolved mechanisms to down-regulate or circumvent the antiviral pathways. For example, it has been found that in patients infected with HIV-1, the 2-5A synthetase/RNase L antiviral defense pathway is down-regulated. RNase L is inactivated in HIV-1 infected cells by the overexpression of a naturally occurring RNase L inhibitor, which blocks the binding of 2-5A to RNase L, thereby preventing RNase L activation. It has been shown that a synthetic 2-5A agonist activates RNase L and inhibits the synthesis of viral RNA and the production of infectious HIV-1 particles. Accordingly, the antiviral effect of synthetic 2′,5′-oligoadelylate compounds is considered to be based on a counteraction of the down-regulated 2-5A synthetase/RNase L pathways by activation of RNase L (Dimitrova et al., AIDS Res Hum Retroviruses 23(1): 123-134, 2007).
Various 2′,5′-oligoadenylate derivative compounds have been described with antiviral effects. EP 0 630 249 describes a broad range of 2′,5′-oligoadenylate derivative compounds and their use for the inhibition of viral infection in a mammal. The compounds are described to activate the intracellular latent RNase L and also inhibit the action of viral DNA polymerases. WO98/56385 describes base-modified derivatives of 2′,5′-oligoadenylate and antiviral uses thereof. WO89/12380 relates to the therapeutic uses of 2′,5′-oligoadenylate derivatives in the treatment of chronic infection with viruses including but not limited to human B-lymphotropic virus (HBLV).
U.S. Pat. No. 4,464,359 describes 2′,5′-oligoadenylates and derivatives thereof as an antiviral material effective against Herpes simplex infection and effective in inhibiting the transformation of cells infected with Epstein Barr virus.
U.S. Pat. No. 4,924,624 relates to 2′,5′-phosphorothioate oligoadenylates and a method of inhibiting viral infection in plants. U.S. Pat. No. 4,981,957 relates to oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini and to their biological uses as mediators of the action of interferon and as antiviral agents.
It has been reported that in chronic fatigue syndrome patients, the 2-5A synthetase/RNase L pathway appears to be up-regulated with increased levels of bioactive 2-5A synthetase, elevated bioactive 2-5A levels and increased activity of the RNase L enzyme (Suhadolnik et al., Clin. Infect. Dis. 18: S96-S104, 1994; Suhadolnik et al., In Vivo 8: 599-604, 1994; Nijs and De Meirleir In Vivo 19(6): 1013-21, 2005).
There remains a need for compounds for use in the treatment of CFS and in the treatment of infection by a gamma-retrovirus.